Colonic transcriptomic data of interleukin-10-deficient mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE264294 | GEO | 2025/05/01
REPOSITORIES: GEO
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Project description:Inflammatory bowel disease (IBD) is a chronic relapsing autoimmune disease of gastrointestinal tract (GI), involving in dysfunction of a variety of genes, such as Interleukin (IL)-10. Intense researches have demonstrated that IL10-deficient (IL10-/-) mice gradually exhibits features of spontaneous enterocolitis at 4-8 weeks of age and IL-10 is a significant immunomodulator in intestinal tract. Therefore, IL10-/- mice have become a classic model of enterocolitis to study the pathogenesis of IBD. The prevailing view is that IL10 deficiency leads to abnormal activation of immune cells and overproduction of a range of inflammation-inducing cytokines, which results in the persistence of intestinal inflammation in the mice. To uncover the role of the underlying molecular mechanisms involved in IL10-/--associated chronic enterocolitis, we construct IL10-deficient mice, sequence transcriptome and proteome of colon tissues from the mice with colitis and perform an integrated analysis of the two omics in this study. Mechanically, we might find out several novel signaling pathways or new therapeutic targets for IBD according to this combined analysis.
2024-04-26 | PXD051806 |
Project description:That commensal bacteria can influence intestinal inflammation has been observed using other models of chronic colitis. Loss of IL-10, a major immunosuppressive cytokine, induces spontaneous colitis in mice. The incidence of spontaneous polyp formation in IL-10-deficient mice was also completely eliminated in the absence of STING We used microarrays to evaluate the inflammatory cytokine expression in the colon from IL10 KO mice and IL10/STING KO mice.
2018-02-01 | GSE107810 | GEO
Project description:Background and Aims: In the interleukin-10-deficient (Il10-/-) mouse model of IBD, 10 quantitative trait loci (QTL) have been shown to be associated with colitis susceptibility by linkage analyses on experimental crosses of highly susceptible C3H/HeJBir (C3Bir)-Il10-/- and partially resistant C57BL/6J (B6)-Il10-/- mice. The strongest locus (C3Bir-derived cytokine deficiency-induced colitis susceptibility [Cdcs]1 on Chromosome [Chr] 3) controlled multiple colitogenic subphenotypes and contributed the vast majority to the phenotypic variance in cecum and colon. This was demonstrated by interval-specific Chr 3 congenic mice wherein defined regions of Cdcs1 from C3Bir or B6 were bred into the IL-10-deficient reciprocal background and altered the susceptible or resistant phenotype. Furthermore, this locus likely acts by inducing innate hypo- and adaptive hyperresponsiveness, associated with impaired NFΚB responses of macrophages. The aim of the present study was to dissect the complexity of Cdcs1 by further development and characterization of reciprocal Cdcs1 congenic strains and to identify potential candidate genes in the congenic interval. Material and Methods: In total, 15 reciprocal congenic strains were generated from Il10-/- mice of either C3H/HeJBir or C57BL/6J backgrounds by 10 cycles of backcrossing. Colitis activity was monitored by histological grading. Candidate genes were identified by fine mapping of congenic intervals, sequencing, microarray analysis and a high-throughput real-time RT-PCR approach using bone marrow-derived macrophages. Results: Within the originally identified Cdcs1-interval, three independent regions were detected that likely contain susceptibility-determining genetic factors (Cdcs1.1, Cdcs1.2, and Cdcs1.3). Combining results of candidate gene approaches revealed Fcgr1, Cnn3, Larp7, and Alpk1 as highly attractive candidate genes with polymorphisms in coding or regulatory regions and expression differences between susceptible and resistant mouse strains. Conclusions: Subcongenic analysis of the major susceptibility locus Cdcs1 on mouse chromosome 3 revealed a complex genetic structure. Candidate gene approaches revealed attractive genes within the identified regions with homologs that are located in human susceptibility regions for IBD. Experiment Overall Design: Bone marrow derived macrophages (BMDM) of colitis susceptible C3Bir-Il10-/- and colitis resistant B6-Il10-/- as well as the Il10-/- reciprocal congenic strains CB-R1 (C3Bir genetic background carrying a long congenic chromosome 3 element containing Cdcs1 from B6, rendering this formerly susceptible background resistant) and BC-R3 (B6 genetic background that carries the Cdcs1-region of C3Bir) were cultured and stimulated with flagellin or left unstimulated. BMDM were obtained from 3 male mice per genotype and cultured in polystyrene 6-well culture plates. Before RNA-isolation, 3 wells per plate were stimulated with Cbir1 flagellin (and subsequently pooled for RNA isolation), the other 3 wells left unstimulated (and also pooled). In total, these experiments were replicated three times in order to perform microarray analyses in triplicates.
2009-10-09 | E-GEOD-15318 | biostudies-arrayexpress
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. Gene expression profiles were established for normal miR-21-/- mice and wild type c57BL/6 mice (WT). Total of 6 samples with replicates were included in this study.
2014-07-23 | E-GEOD-59648 | biostudies-arrayexpress
Project description:We have compared mRNA expression in full-thickness mouse colon between wildtype mice and mice with a genetic deletion in tumor necrosis factor receptor 1 (TNFR1, encoded by the Tnfrsf1a gene). This experiment was motivated by our observation that Il10-/- Tnfr1-/- double-knockout mice develop very-early-onset colitis at the time of weaning, significantly earlier than disease onset in Il10-/- single-knockout mice. This suggests that TNFR1 mediates protection from colitis. To understand these protective mechanisms at the transcript level in a non-inflammatory context, we performed transcriptome profiling (mRNA-Seq) on colons from 12-week-old Tnfr1-/- mice, which do not develop colitis, and wildtype littermates. These experiments revealed that an estimated 510 transcripts were upregulated and 377 downregulated in colonic tissue of Tnfr1-/- mice. We aggregated the transcript information to calculate gene expression and performed gene set enrichment analysis to identify signaling pathways altered in Tnfr1-/- mice. When queried against a high-confidence set of 50 signaling pathways, the Tnfr1-/- gene expression profile was associated with reduced mitosis and increased glycolysis, transforming growth factor beta signaling, DNA repair, and reactive oxygen species signaling. Gene ontological analysis classified some of the differentially expressed genes into cytokines, junctional proteins, and transcription factors, but within these groups there was no consensus on the direction of regulation. We also examined how differentially expressed transcripts (called the TNFR1-regulated transcriptome) compared to differentially expressed colonic transcripts from previously collected Tnfr2-/- animals (or the TNFR2-regulated transcriptome, available at the NCBI Gene Expression Omnibus under the accession GSE65408). The raw data were re-analyzed with the current pipeline to enable comparison. There was almost no correlation between TNFR1- and TNFR2-regulated transcripts. Only 30 (~3%) TNFR1-regulated transcripts were also TNFR2-regulated transcripts, and ~4% of the TNFR2-regulated genes were also TNFR1-regulated genes. Of the few co-regulated transcripts, there was a significant negative correlation in their direction of regulation in Tnfr1-/- versus Tnfr2-/- colons. Collectively these results indicate that TNFR1 and TNFR2 have mostly different and opposing effects on gene expression in the mouse colon. MANUSCRIPT ABSTRACT: BACKGROUND & AIMS: Very-early-onset inflammatory bowel disease (VEO-IBD) is a devastating disease beginning in early childhood, refractory to anti-tumor necrosis factor (anti-TNF) therapies, and associated with mutations in the interleukin 10 (IL-10) pathway. Contrary to mainstream clinical practice, cellular and animal studies have shown beneficial roles of TNF signaling in colitis, but how these roles are encoded through TNF’s receptors remains unknown. Here we examined the role of TNF receptor 1 (TNFR1, or p55) in modulating the onset and severity of colitis in the interleukin 10 (IL-10)-deficient mouse model. METHODS: Colitis severity was compared between Il10-/- Tnfr1-/- and Il10-/-- littermate mice at 2-12 weeks of age. To assess dysbiosis as a potential pathogenic mechanism, Il10-/- Tnfr1-/- mice were treated with neomycin and metronidazole and their cecal contents analyzed by 16S rRNA sequencing. Gene expression, barrier function, and epithelial proliferation and apoptosis were examined in adult colitis-free Tnfr1-/- wildtype littermates. RESULTS: In contrast to relatively healthy Il10-/- mice, Il10-/- Tnfr1-/- mice developed severe, antibiotic-treatable colitis shortly after weaning. Microbiotal composition was similar between Il10‑/- Tnfr1-/- mice and Il10-/- littermate controls. Tnfr1-/- mice expressed transcripts associated with reactive oxygen species and DNA repair pathways. Tnfr1-/- mice exhibited focal areas of crypt branching, higher colonic epithelial permeability, and hallmarks of DNA damage. CONCLUSIONS: TNFR1 promotes epithelial homeostasis and regulates commensal exposure. The lack of TNFR1 accelerates the onset and severity of IBD in the absence of tolerogenic signaling (i.e., lack of IL-10). Il10-/- Tnfr1-/- mice may serve as a valuable model of very-early-onset IBD (VEO-IBD).
2019-03-15 | GSE107933 | GEO
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. miRNAs expression was accesed for acute and chronic murine model of colitis induced by DSS or TNBS.Total of 20 samples with duplicates were analyed in this study.
2014-07-23 | E-GEOD-59650 | biostudies-arrayexpress
Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. miRNAs expression was accesed for acute and chronic murine model of colitis induced by DSS or TNBS.Total of 20 samples with duplicates were analyed in this study.
2014-07-23 | E-GEOD-59649 | biostudies-arrayexpress
Project description:Intestinal microbial dysbiosis is associated with Crohn’s disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. To evaluate causality and mechanisms of disease, we conducted a systems level study of the interactions between the gut microbiota and host in new-onset pediatric patients. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. A downregulation of mitochondrial proteins implicated in H2S detoxification was observed, while the relative abundance of H2S microbial producers was increased. Network correlation analysis identified Atopobium parvulum as the central hub of H2S producers. Gnotobiotic and conventionalized colitis-susceptible interleukin-10-deficient (Il10-/-) mice demonstrated that A. parvulum induced colitis, a phenotype requiring the presence of the intestinal microbiota. Administration of bismuth, a H2S scavenger, prevented A. parvulum-induced colitis in Il10-/- mice. This study identified host-microbiota interactions that are disturbed in CD patients providing mechanistic insights on CD pathogenesis.
2016-09-29 | PXD002882 | Pride
Project description:Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulator of immune cells functions, using a biobank IBD patient cohort as well as the oral dextran sulfate sodium (DSS) exposure mouse IBD colitis, and, in parallel, the oral Salmonella exposure mouse colitis models. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both mouse models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis, i.e., the Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not cause mouse colon bacterial dysbiosis based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice appeared nominal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection response both prior and after the DSS exposure. The data indicate that Parp14 has an important role in the maintenance of epithelial barrier integrity in colitis, and that Parp14 may have functions also outside the immune cell compartment. The prognostic and predictive biomarker potential of Parp14 as well as its mutational landscape in IBD merits further investigation.
2024-01-13 | GSE252812 | GEO
Project description:Microbial dysbiosis has been identified in adult inflammatory bowel disease (IBD) patients. However, microbial composition and functional interplay between host genetics and microorganisms in early IBD onset remain poorly defined. Here, we identified and demonstrated the causal effect of Atopobium parvulum and the gut microbiota in pediatric IBD. Microbiota and proteomic profiling revealed that the abundance of A. parvulum, a potent H2S producer, was associated with increased disease severity and a concurrent reduction in the expression of the host H2S detoxification pathway. In the Il10-/- mouse model of inflammation, A. parvulum induced severe pancolitis that was dependent on the presence of the gut microbiota. In addition, we demonstrated that administration of bismuth, an H2S scavenger, prevented A. parvulum-induced colitis. Our findings identified Atopobium parvulum as a major mediator of inflammation severity, and revealed an alteration of the balance between the production and detoxification of H2S in the gastrointestinal tract.
2022-02-22 | PXD000690 | Pride